CN107991403B - The analysis method of genotoxicity impurity 6,8- dicloro caprylate ethyl ester in a kind of lipoic acid - Google Patents
The analysis method of genotoxicity impurity 6,8- dicloro caprylate ethyl ester in a kind of lipoic acid Download PDFInfo
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Abstract
The invention discloses a kind of analysis methods of genotoxicity impurity 6,8-dichloro-octanoic acid ethyl ester in lipoic acid, are detected using internal standard method for gas chromatography technology to the 6,8-dichloro-octanoic acid ethyl ester in the pungent sample solution of sulfuric acid；The testing conditions of gas-chromatography are as follows: chromatographic column: 30m × 0.25mm × 0.25 μm DB-WAX, stationary phase are polyethylene glycol, and carrier gas is high pure nitrogen；Column temperature: it 100 DEG C of initial temperature, maintains 2 minutes, then 230 DEG C is warming up to 20 DEG C of rates per minute, in 230 DEG C of maintenance 5min；Mass Spectrometry Conditions are as follows: ion source voltage: -70eV, ion source temperature: 230 DEG C, level four bars temperature: 150 DEG C, interface temperature: 280 DEG C.The analysis method fast, high sensitivity advantage with analysis speed.
Description
Technical field
Present invention relates particularly to genotoxicity impurity 6,8- in a kind of lipoic acid based on Gas chromatographyMass spectrometry
The analysis method of dicloro caprylate ethyl ester.
Technical background
Genotoxicity impurity, which refers to, can directly or indirectly damage DNA, lead to gene mutation or the substance with carcinogenic tendency.
Genotoxicity impurity feature is that the damage of human genetic material can be caused when concentration is very low, has mutagenicity and carcinogenic
Property, the health of the mankind is seriously threatened during medication.In recent years, also more and more to occur because in marketed products
In, it finds the genotoxicity impurity residual of trace and large-scale malpractice occurs, the case recalled by force by FDA, administration
Factory causes huge economic loss.The vilasette ingot event of such as 2007 Roche Holding Ags, due to methanesulfonic acid second in drug
Ester seriously transfinites, and causes several patient's DNA sequence dnas abnormal, and final products are all recalled, and European drug evaluations office suspends Roche
All marketing activities re-start assessment to its new process, and list again after doing toxicity research.It can be seen that in order to avoid
Genotoxicity impurity is passively taken in, and ensures drug quality and the drug safety of the masses, develops the standard of drug gene toxic impurities
Really identification and monitoring method have very important significance.In recent years, the regulatory authorities of various countries, as EMEA, FDA, ICH phase are secondary
Guideline of the cloth for genotoxicity impurity.Due to lacking genotoxicity impurity safety data branch in current global range
It holds, relevant laws and regulations are using caution structure as the outstanding feature of latent gene toxic impurities.Since genotoxicity defects inspecting exists
Particular/special requirement, analysis method and other impurities are presented in sensitivity, selectivity, determinand stability, matrix complexity etc.
The different feature of testing requirements.The analytical technology of drug gene toxic impurities is still very not perfect at present.Cause enterprise to gene
Toxic impurities judgement and grasp be not comprehensive, causes to research and develop the problems such as at high cost and drug legislation examination & approval analysis needs " hair benefit ", shadow
Ring research and development speed, the quality of product and international competitiveness.
6,8-dichloro-octanoic acid ethyl ester is important chemical intermediate, belongs to noxious material, in a variety of medicine production process
Exist as the form of intermediate or by-product, it is safe for guarantee drug for the quality control of such genotoxicity impurity
It is extremely important, in production process of lipoic acid, due to the use of related reagent, generate the 6,8-dichloro-octanoic acid ethyl ester of trace, drug
The pre-treatment of sample, including extract, separation and chromatographic condition etc. can all influence the accuracy of result.Therefore, it is necessary to establish point
Analysis method realizes the quantitative analysis accurately and quickly of the substance.But the analysis skill about 6,8- dicloro caprylate ethyl ester at present
Art has not been reported.
Summary of the invention
For above-mentioned the technical problems existing in the prior art, the object of the present invention is to provide one kind to be based on gas-chromatography-
The analysis method of genotoxicity impurity 6,8- dicloro caprylate ethyl ester in the lipoic acid of mass spectrometric hyphenated technique.The analysis method, which has, divides
Analyse that speed is fast, advantage of high sensitivity.
In order to solve the above technical problems, the technical solution of the present invention is as follows:
Genotoxicity impurity 6,8- dicloro caprylate ethyl ester in a kind of lipoic acid based on Gas chromatographyMass spectrometry
Analysis method examines the 6,8-dichloro-octanoic acid ethyl ester in the pungent sample solution of sulfuric acid using internal standard method for gas chromatography technology
It surveys；
The testing conditions of gas-chromatography are as follows: chromatographic column: 30m × 0.25mm × 0.25 μm DB-WAX, stationary phase are poly- second two
Alcohol, carrier gas are high pure nitrogen；Column temperature: it 100 DEG C of initial temperature, maintains 2 minutes, is then warming up to 20 DEG C of rates per minute
230 DEG C, in 230 DEG C of maintenance 5min；
Mass Spectrometry Conditions are as follows: ion source voltage: -70eV, ion source temperature: 230 DEG C, level four bars temperature: 150 DEG C, interface temperature
Degree: 280 DEG C.
Preferably, the injector temperature of gas-chromatography is 280 DEG C, split ratio 2:1.
Preferably, the flow rate of carrier gas of gas-chromatography is 1.0mL/min, and sampling volume is 1.0 μ L.
Preferably, the retarder thinner of the pungent sample solution of the sulfuric acid is methanol.The drug and 6,8- dicloro caprylate ethyl ester are all
Methanol can be dissolved in.
Preferably, the analysis method includes the preparation steps of test solution, reference substance stock solution and reference substance solution,
Test solution is the pungent solution of sulfuric acid, and concentration 10mg/mL, it is that 6,8-dichloro-octanoic acid ethyl ester is molten that reference substance, which stores liquor,
Liquid, concentration are 10.0 μ g/mL；Reference substance solution is diluted to reference substance stock solution, concentration 1000ng/mL.
It is further preferred that the analysis method further includes individually into the step of the retarder thinner of the pungent sample solution of the sulfuric acid
Suddenly,
To prove whether there is the presence of interfering substance in the retarder thinner.
It is further preferred that the analysis method further includes the steps that individually into test solution, to prove that test sample is molten
Other components in liquid are noiseless to the test of measured object.
It is further preferred that being diluted to reference substance solution, compound concentration is the sensitivity solution of 800ng/mL, accurate
It measures 1 μ L of sensitivity solution and injects gas chromatograph-mass spectrometer, make the signal-to-noise ratio of 6,8-dichloro-octanoic acid ethyl ester peak value not less than 10, measurement should
The sensitivity of method.
It is further preferred that the detection of the analysis method is limited to 6ppm, it is quantitatively limited to 20ppm.
It is further preferred that the linear equation of the analysis method is y=8.9313x -176.69, R2=0.999, linearly
Concentration range is 200-5000ng/mL.
Beneficial effects of the present invention:
The detection of method of the invention is limited to 6ppm, is quantitatively limited to 20ppm, may be implemented to the low content 6 in lipoic acid,
8- dicloro caprylate ethyl ester is qualitatively and quantitatively detected.
The range of linearity of the invention is 200-5000ng/mL, the coefficient R of linear equation2It is 0.999, may be implemented
Quantitative detection in larger concentration range.The recovery of standard addition of method has preferable accuracy in detection all near 100%.
Same reference substance solution is detected in different time, the RSD of object peak area response is 1.23%, table
The reference substance solution and detection method of bright preparation are all with good stability, smaller by external environmental interference.
Detailed description of the invention
The accompanying drawings constituting a part of this application is used to provide further understanding of the present application, and the application's shows
Meaning property embodiment and its explanation are not constituted an undue limitation on the present application for explaining the application.
Fig. 1 is the full scan chromatogram of test solution；
Fig. 2 is the linearity curve of analysis method of the present invention.
Specific embodiment
It is noted that following detailed description is all illustrative, it is intended to provide further instruction to the application.Unless another
It indicates, all technical and scientific terms used herein has usual with the application person of an ordinary skill in the technical field
The identical meanings of understanding.
It should be noted that term used herein above is merely to describe specific embodiment, and be not intended to restricted root
According to the illustrative embodiments of the application.As used herein, unless the context clearly indicates otherwise, otherwise singular
Also it is intended to include plural form, additionally, it should be understood that, when in the present specification using term "comprising" and/or " packet
Include " when, indicate existing characteristics, step, operation, device, component and/or their combination.
Introduction
1. the result of verifying
2, chromatographic condition and method
(1) gas chromatograph and gas phase condition
Gas chromatograph: AgiLent 7890-5973N
Chromatographic column: 30m × 0.25mm × 0.25 μm DB-WAX
Stationary phase: polyethylene glycol
Column temperature:, maintaining 2 minutes by 100 DEG C of initial temperature, is warming up to 230 DEG C with 20 DEG C of rates per minute, maintains 5min.
Injector temperature: 280 DEG C, split ratio: 2:1, carrier gas: high-purity helium,
Flow velocity: 1.0mL/min, sampling volume: 1.0 μ L.
(2) mass spectrometer and Mass Spectrometry Conditions
Each impurity quantitative mass spectral condition is shown in Table 1.
Each impurity quantitative mass spectral condition of table 1
| Acquisition mode | Salbutamol Selected Ion Monitoring (SIM) | Ion source module | Electron bombardment (EI) |
| Ion source voltage | -70eV | Ion source temperature | 230℃ |
| Quadrupole rod (MS) temperature | 150℃ | Interface temperature | 280℃ |
(3) the ion pair peak extracted
The quantitative quasi-molecular ions of each impurity mass spectrum is shown in Table 2.
The quantitative quasi-molecular ions of each impurity mass spectrum of table 2
| Compound name | Quota ion | Qualitative ion |
| 6,8- dicloro caprylate ethyl ester | 88 | 95,123,195 |
(4) preparation of solution
Retarder thinner: methanol
Test solution: taking lipoic acid 100.0mg, accurately weighed, sets in 10mL measuring bottle, adds retarder thinner dissolution and constant volume
It to scale, shakes up, as test solution.
Reference substance stock solution: taking 6,8-dichloro-octanoic acid ethyl ester 100.0mg, accurately weighed, is placed in 100mL measuring bottle, adds dilute
It releases solvent and dissolves and be diluted to scale, shake up, as stock solution 1.Precision measures 1.0mL stock solution 1, is placed in 100mL measuring bottle,
Add retarder thinner to be diluted to scale, shake up, as reference substance stock solution, concentration is 10.0 μ g/mL.
Reference substance solution: precision measures reference substance stock solution 1.0mL, sets in 10mL measuring bottle, retarder thinner is added to be diluted to quarter
Degree, as reference substance solution, (concentration 1000ng/mL).
Sensitivity solution: precision measures reference substance solution 8.0mL, sets in 10mL measuring bottle, retarder thinner is added to be diluted to scale,
As sensitivity solution.(concentration 800ng/mL)
Verification Project
1, specificity
Operating procedure
A) individually into retarder thinner solution, it was demonstrated that the solution tests measured object noiseless.
B) individually into test solution, it was demonstrated that the other components reply measured object measurement in the solution is noiseless
C) reference substance stock solution 1 is taken, retarder thinner dilutes 20 times, takes 1.0 μ L sample introductions.Record chromatogram and mass spectrogram.
D) mark-on solution: test sample adds impurity, takes 1.0 μ L sample introductions.Record chromatogram and mass spectrogram.
Expected standard:
Other components reply measured object measurement in blank solution and sample is noiseless.
Conclusion: blank solution is noiseless to defects inspecting, and other impurities are to the detection of target compound without dry in test sample
It disturbs, as shown in Figure 1.
2, sensitivity
Expected standard:
Precision measures 1 μ L of sensitivity solution and injects gas chromatograph-mass spectrometer, records ion flow graph, 6,8-dichloro-octanoic acid ethyl ester peak value
Signal-to-noise ratio cannot be less than 10.
Conclusion: precision measures 1 μ L of sensitivity solution and injects gas chromatograph-mass spectrometer, the signal-to-noise ratio of 6,8-dichloro-octanoic acid ethyl ester peak value
It is 65.5.
3, system suitability
Operating procedure
Take 1 μ L sample introduction of reference substance solution, 6 needle of continuous sample introduction, the RSD value of the peak area response of target compound such as table 3
It is shown.
3 system suitability result of table
4, detection limit and quantitative limit
It is accurate to prepare measured object standard solution, it is gradually diluted to a certain concentration and sample introduction, signal-to-noise ratio (S/N) is 3 or so
Sample concentration be detect limit concentration, detection limit continuously into 3 needles；Signal-to-noise ratio is quantitative limit in the concentration of 10~15 sample
Concentration, 6 needle of quantitative limit continuous sample introduction；The ratio of detection limit concentration and sample theoretical concentration is to detect limit；Quantitative limit concentration with
The ratio of sample theoretical concentration is quantitative limit, and calculates the corresponding signal-to-noise ratio RSD value of quantitative limit.
Operating procedure
Precision measures reference substance solution and is diluted to the solution that concentration is 60ng/mL, 200ng/mL step by step in right amount, as detection
The stand-by solution of limit and quantitative limit.
Blank solution and each 1.0 μ L of above-mentioned solution are taken, makings chromatograph is injected separately into, records ion flow graph.
Test result.
The corresponding signal-to-noise ratio of measured object peak value is recorded, the RSD value of the continuous 6 needle signal-to-noise ratio of quantitative limit is calculated, as a result such as 4 institute of table
Show.
The detection limit test result of table 4
5 quantitative limit test result of table
5, linear and range
Operating procedure
Linear solvent 1: precision measures reference substance stock solution 0.2mL, is placed in 10mL measuring bottle, is diluted to quarter with retarder thinner
Degree, shakes up.
Linear solvent 2: precision measures reference substance stock solution 0.5mL, is placed in 10mL measuring bottle, is diluted to quarter with retarder thinner
Degree, shakes up.
Linear solvent 3: precision measures reference substance stock solution 1.0mL, is placed in 10mL measuring bottle, is diluted to quarter with retarder thinner
Degree, shakes up.
Linear solvent 4: precision measures reference substance stock solution 1.2mL, is placed in 10mL measuring bottle, is diluted to quarter with retarder thinner
Degree, shakes up.
Linear solvent 5: precision measures reference substance stock solution 2.0mL, is placed in 10mL measuring bottle, is diluted to quarter with retarder thinner
Degree, shakes up.
Linear solvent 6: precision measures reference substance stock solution 5.0mL, is placed in 10mL measuring bottle, is diluted to quarter with retarder thinner
Degree, shakes up.
Each 1 μ L sample introduction of above-mentioned linear solvent is taken, ion flow graph is recorded.Linearity curve is as shown in Figure 2.
The 6 linear result of 6,8- dicloro caprylate ethyl ester of table
6, method precision
Operation requires
A) it takes lipoic acid to claim sample and is configured to the test solution containing each 100% limit value of target compound, as method precision
Degree test solution, prepares 6 parts altogether.
B) content, the rate of recovery of calculating target compound and the RSD and RSD of the rate of recovery answer≤10.0%.
Operating procedure
Precision weighs lipoic acid 100.0mg, sets in 10mL measuring bottle, then accurate addition reference substance stock solution 1.0mL, then plus
Retarder thinner is diluted to scale, shakes up, and as test solution, test result is shown in Table 7.
7 method precision test result of table
7, method accuracy
Purpose
Determine the measurement result of the chromatographic process and the difference of true value (additional amount).To confirm whether this method can be with
Obtain accurate test result.
Operating procedure
Precision weighs lipoic acid 100.0mg, is placed in 10mL measuring bottle, then accurate addition reference substance stock solution 0.8mL, then plus
Retarder thinner is diluted to scale, shakes up and tests solution as 80% limit.
Precision weighs lipoic acid 100.0mg, is placed in 10mL measuring bottle, then accurate addition reference substance stock solution 1.0mL, then plus
Retarder thinner is diluted to scale, shakes up, and tests solution as 100% limit.
Precision weighs lipoic acid 100.0mg, is placed in 10mL measuring bottle, then accurate addition reference substance stock solution 1.2mL, then plus
Retarder thinner is diluted to scale, shakes up, and tests solution as 120% limit.
Expected standard
The rate of recovery should be between 80%~120%, and test result is shown in Table 8.
8 6,8- dicloro caprylate ethyl ester accuracy test result of table
Note: N.D. expression is not detected in table.
8, stability of solution
1 μ l sample introduction of reference substance solution is taken, every 2h sample introduction is primary, altogether sample introduction 6 times, with the RSD of object peak area response
The stability of solution is evaluated, experimental result is shown in Table 9.
9 6,8- dicloro caprylate ethyl ester stability of solution result of table
9, sample detection
Operating procedure
Lipoic acid sample solution: accurately weighed 1,2 batch sample 100.0mg, 100.0mg respectively are respectively placed in 10mL's
In measuring bottle, then plus retarder thinner dissolve and be diluted to scale, shake up, sample introduction test, test result is shown in Table 10.
10 sample detection result of table
The foregoing is merely preferred embodiment of the present application, are not intended to limit this application, for the skill of this field
For art personnel, various changes and changes are possible in this application.Within the spirit and principles of this application, made any to repair
Change, equivalent replacement, improvement etc., should be included within the scope of protection of this application.
Claims (9)
1. the analysis method of genotoxicity impurity 6,8-dichloro-octanoic acid ethyl ester in a kind of lipoic acid, it is characterised in that: use gas phase
Chromatography and mass spectrometric hyphenated technique detect the 6,8- dicloro caprylate ethyl ester in the pungent sample solution of sulfuric acid；The detection of gas-chromatography
Condition are as follows: chromatographic column: 30m × 0.25mm × 0.25 μm DB-WAX, stationary phase are polyethylene glycol, and carrier gas is high pure nitrogen；Column
Temperature: it 100 DEG C of initial temperature, maintains 2 minutes, then 230 DEG C is warming up to 20 DEG C of rates per minute, in 230 DEG C of maintenance 5min；
Mass Spectrometry Conditions are as follows: ion source voltage: -70eV, ion source temperature: 230 DEG C, level four bars temperature: 150 DEG C, interface temperature: 280 DEG C；
The retarder thinner of the pungent sample solution of sulfuric acid is methanol.
2. analysis method according to claim 1, it is characterised in that: the injector temperature of gas-chromatography is 280 DEG C, is shunted
Than for 2:1.
3. analysis method according to claim 1, it is characterised in that: the flow rate of carrier gas of gas-chromatography is 1.0mL/min, into
Sample volume is 1.0 μ L.
4. analysis method according to claim 1, it is characterised in that: the analysis method includes test solution, control
The preparation steps of product stock solution and reference substance solution, test solution are the pungent solution of sulfuric acid, concentration 10mg/mL, reference substance
Reserve liquor is 6,8-dichloro-octanoic acid ethyl ester solution, and concentration is 10.0 μ g/mL；Reference substance solution is to reference substance stock solution
It is diluted, concentration 1000ng/mL.
5. analysis method according to claim 4, it is characterised in that: further include individually into the pungent sample solution of the sulfuric acid
The step of retarder thinner, to prove whether there is the presence of interfering substance in the retarder thinner.
6. analysis method according to claim 4, it is characterised in that: further include the steps that individually into test solution, with
Prove that the other components in test solution are noiseless to the test of measured object.
7. analysis method according to claim 4, it is characterised in that: be diluted to reference substance solution, compound concentration is
The sensitivity solution of 800ng/mL, precision measure 1 μ L of sensitivity solution and inject gas chromatograph-mass spectrometer, make 6,8-dichloro-octanoic acid ethyl ester peak
The signal-to-noise ratio of value is not less than 10, measures the sensitivity of this method.
8. analysis method according to claim 1, it is characterised in that: the detection of the analysis method is limited to 6ppm, quantitative
It is limited to 20ppm.
9. analysis method according to claim 1, it is characterised in that: the linear equation of the analysis method is y=
8.9313x -176.69, R2=0.999, linear concentration range is 200-5000ng/mL.
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